Steroid guanylhydrazones and production thereof



3,268,520 STEROID GUANYLHYDRAZONES AND PRODUCTHON THEREOF SiegismnndSchlitz and Karl-Heinz Meyer, Wuppertal- Elberfeld, Kurt Stoepel,Wuppertal-Vohwinkel, and Hans-Gunther Kroneberg, Haan, Rhineland,Germany, assignors to Farbenfabriken Bayer Aktiengesellschaft,Leverkusen, Germany, a corporation of Germany No Drawing. Filed Jan. 15,1964, Ser. No. 337,739 Claims priority, applicatigm Germany, Jan. 23,1963,

8,830 11 Claims. (Cl. 260-2395) The present invention relates to newsteroid guanylhydrazones obtained from ZO-carbonyl steroids and theirproduction by methods hereinafter described. The new products and theiracid salts exhibit useful cardio-tonic activity.

The action of aminoguanidine on steroids which contain a carbonyl groupat the 3- or 17-position has already been described [1. Barnett and C.I. O. R. Morris, Biochemical Journal 40, 450 (1946), and M. Pesez, J.Bartos, I. Mathieu and J. Valls, Bull. Soc. Chim. France, 1958, 488].The reaction products have been employed for physical measurements.However, reactions with steroids having a keto group at the 20-positionand the novel products thereby resulting are not known and have notheretofore been described.

It has now been found that compounds of the following formula possessvaluable biological properties:

in which B is selected from the group consisting of hydrogen, alkyl of 1to 6 carbon atoms, nitro and 11 being 2-4, and R and R each beingseparately alkyl of 1 to 6 carbon atoms and linked together to form aring with the N atom,

Z is selected from the group consisting of hydrogen, hydroxyl and adouble bond to U, U is selected from the group consisting of H and Htogether With a double bond to Z, and D is selected from the groupconsisting of hydrogen and 11, R and R being as above defined.

These novel compounds exhibit cardio-tonic activity by themselves assuch or in the form of their salts with non-toxic pharmaceuticallyacceptable inorganic or organic acids. Suitable acids are, for instance,acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid,succinic acid, tartaric acid, citric acid, salicylic acid,naphthalene-1,5-disulfonic acid, phosphoric acid, hydrochloric acid andthe like.

United States Patent In accordance with the invention, the novelcompounds are prepared by:

(a) reacting 20-carbonyl-steroids with aminoguanidines or their salts,

(b) reacting thiosemicarbazones of 20-carbonyl-stcroids with amines,

(c) reacting S-alkylthio-isothiosemicarbazones carbonyl-steriods withamines, or

(d) reacting hydrazones of ZO-carbonyl-steroids With cyanamides.

The thiosemicarbazones, S-alkyl-isothiosemicarbazones and hydrazones ofZO-carbonyl-steroids which can be employed as the starting materials areobtained by the reaction of 20-carbonyl-steroids with thiosemicarbazidesor S-alkyl-isothiosemicarbazid-es or thiosemicarbazides and alkylhalides or hydrazines.

The invention is illustrated by the following nonlimitative examples.

Example 1 4 g. of pregn-5-en-3-ol-20-one are dissolved in methanol. Asolution of 9.3 g. of aminoguanidine hy- 5 g. of pregn-5-en-3-ol-20-oneare dissolved in absolute tetrahydrofuran, 1 g. of sodamide moistenedwith xylene is introduced into this solution and boiled under reflux for3 hours. When the evolution of ammonia has ceased, 2.8 g. of,B-diethylamino-ethyl chloride are added, and it is subsequently boiledovernight while stirring. It is evaporated to dryness and the residue isdissolved in dilute acetic acid. The solution in acetic acid is renderedalkaline, decanted, and the residual viscous oil is dissolved inchloroform. It is dried, evaporated and 5.8 g. of3-(B-diethylaminoethoxy)-5-pregnene 20 one are obtained. 5 g. of thisoil are dissolved in methanol, treated with a solution of 12 g. ofaminoguanidine hydrogen carbonate in methanolie hydrochloric acid andleft to stand at room temperature for 2 days while acidic to Congo red.It is neutralized with solid sodium bicarbonate, filtered and evaporatedto dryness. The residue is dissolved in dilute acetic acid, the solutionin acetic acid is rendered alkaline and extracted by shaking Withchloroform. After drying and evaporation, hydrochloric acid in ether isadded to the solution of the residue in dry alcohol in order toprecipitate the dihydrochloride of3-(-diethyl-amino-ethoxy)-5-pregnene-20-guanylhydrazone of melting point25725 8 C.

The dihydrochloride of 3-(fi-pyrrolidino-ethoxy)-5-pregnene-ZO-guanylhydrazone of melting point 260 C is prepared inanalogous manner.

Example 3 3.5 g. of l-(B-diethylamino-ethyl)-3-aminoguanidinehydrochloride and 3 g. of pregn-5-en-3-ol-20-one in 20 ml. of methanolare left to stand at room temperature under nitrogen for 3 days. It ispoured into ether, the separated precipitate is filtered off withsuction, digested with acetone and recrystallized from ethanol. 15 g. ofthe dihydrochloride ofpregn-5-en-3e-ol-20-[l-(fl-diethylaminoethyl)-guanylhydrazone] ofmelting point 286-287" C. (decomp) are obtained.

Example 4 3.5 g. of 1-(fi-pyrrolidino-ethyl)-3-aminoguanidinehydroiodide are dissolved in enough methanolic hydrochloric acid for theresultant solution to have a pH value of 2. A solution of 3 g. ofpregn--en-3-ol-20-one in 200 m1. of methanol is added to it and allowedto stand at room temperature for 3 days. The reaction mixture issubsequently poured into ether, the separated precipitate is boiled outwith acetone and recrystallized from methanol. 2 g. of thedihydrochloride of pregn-S-en-3-ol-20-[1-(fi-pyrrolidino-ethyl)-guanylhydrazone] of melting point30l302 C. (decomp.) are obtained.

The hydrochloride of pregn-5-en-3-ol-20-(l-methylguanylhydrazone) ormelting point 319-320 C. (decomp.) is prepared in analogous manner.

Example 5 A solution of 1.2 g. of 1-nitro-3-aminoguanidine in methanolichydrochloric acid (pH=2) is treated with a solution of 3 g. ofpregn-5-en-3-ol-20-one in 200 ml. of methanol and stirred at roomtemperature for 24 hours. The resultant precipitate is filtered off withsuction and recrystallized from methanol/ether. 3.5 g. of pregn-S-en-3-ol-20-(l-nitro-guanylhydrazone) of melting point 215 C. (decomp.)are obtained.

Example 6 5 g. of 3-acetoxy-pregna-5,16-dien-20-one are dissolved inmethanol, treated with a solution of 12 g. of aminoguanidine hydrogencarbonate in methanolic hydrochloric acid (acidic to Congo red), andleft to stand at room temperature for 3 days. 1.5 g. of thehydrochloride of pregna 5,16 dien-3-ol-20-guanylhydrazone of meltingpoint 314 C. are obtained.

Example 7 3 g. of pregn-5-ene-3,8,17a-diol-20-one are dissolved in 750ml. of hot methanol and treated With a solution of 2.7 g. ofl-(fl-pyrrolidino-ethyl)-3-aminoguanidine hydrochloride in 50 ml. ofmethanol. It is stirred at room temperature under nitrogen for 3 days,the separated crystals are filtered off with suction and recrystallizedfrom methanol With the addition of a little Water.

Yield: 3 g. of the dihydrochloride of pregn-S-ene- 3fi,17oc-Cli0l-20 1-(fl-pyrrolidino-ethyl) -guanylhydrazole] of melting point 267269 C.(decomp.)

1.6 g. of l-ethyl-aminoguanidine hydrochloride are dissolved inmethanolic hydrochloric acid, a solution of 2 g. ofpregn-5-en-3B-ol-20-one in 150 ml. of methanol is added to it, and thereaction solution is left for 3 days before being introduced into ether.The resultant precipitate is filtered oif With suction, boiled out withacetone and recrystallized from methanol.

Yield: 1 g. of the hydrochloride of pregn-5-en-3B-ol-20-(l-ethyl-guanylhydrazone) of melting point 268-270 C. (decomp.)

The hydrochloride of B -nor-pregn-5-en-3,8-ol-20- guanylhydrazone ofmelting point 257 C. (decomp.) is obtained in analogous manner fromB-nor-pregn-S-en- 3,8-ol-20-one and aminoguanidine hydrochloride.

What is claimed is:

4 1. A steroid guanylhydrazone of the formula:

CH3 lfiIH C=N--NEC-NHB in which B is selected from the group consistingof hydrogen,

alkyl of 1 to 6 carbon atoms, nitro and n being 24, and R and R eachbeing separately alkyl of 1 to 6 carbon atoms and linked together toform a ring with the N atom,

Z is selected from the group consisting of hydrogen,

hydroxyl and a double bond to U,

U is selected from the group consisting of H and H together with adouble bond to Z, and

D is selected from the group consisting of hydrogen and References Citedby the Examiner Barnett et al., Biochem. Jour., Vol. 40, pp. 450-53(1946).

Pesez et al.,

Bull. Soc. Chim. France, page 488- (1958).

LEWIS GO'ITS, Primary Examiner.

HENRY A. FRENCH, Assistant Examiner.

1. A STEROID GUANYLHYDRAZONE OF THE FORMULA:
 4. THE COMPOUND3-(B-PYRROLIDINO-ETHOXY)-5-PREGNENE-20-GUANYLDRAZONE DIHYDROCHLORIDE.